2. Academic Validation
  3. Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

  • Sci Transl Med. 2018 May 16;10(441):eaap8307. doi: 10.1126/scitranslmed.aap8307.
Kevin J Frankowski 1,  Chen Wang 2,  Samarjit Patnaik 3,  Frank J Schoenen 1,  Noel Southall 3,  Dandan Li 4,  Yaroslav Teper 4,  Wei Sun 3,  Irawati Kandela 5,  Deqing Hu 6,  Christopher Dextras 3,  Zachary Knotts 4,  Yansong Bian 4,  John Norton 2,  Steve Titus 3,  Marzena A Lewandowska 2,  Yiping Wen 2,  Katherine I Farley 7,  Lesley Mathews Griner 3,  Jamey Sultan 3,  Zhaojing Meng 8,  Ming Zhou 8,  Tomas Vilimas 9,  Astin S Powers 10,  Serguei Kozlov 9,  Kunio Nagashima 11,  Humair S Quadri 4,  Min Fang 12,  Charles Long 2,  Ojus Khanolkar 2,  Warren Chen 2,  Jinsol Kang 2,  Helen Huang 2,  Eric Chow 2,  Esthermanya Goldberg 2,  Coral Feldman 2,  Romi Xi 2,  Hye Rim Kim 13,  Gary Sahagian 12,  Susan J Baserga 7,  Andrew Mazar 5,  Marc Ferrer 3,  Wei Zheng 3,  Ali Shilatifard 6,  Jeffrey Aubé 1,  Udo Rudloff 14,  Juan Jose Marugan 15,  Sui Huang 16
Affiliations

Affiliations

  • 1 Specialized Chemistry Center, The University of Kansas, Lawrence, KS 66047, USA.
  • 2 Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA.
  • 3 NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA.
  • 4 Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 5 Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL 60208, USA.
  • 6 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 7 Departments of Molecular Biophysics and Biochemistry, Genetics, and Therapeutic Radiology, Yale University and Yale School of Medicine, New Haven, CT 06520, USA.
  • 8 Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
  • 9 Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Fort Detrick, Frederick, MD 21702, USA.
  • 10 Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
  • 11 Electron Microscope Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
  • 12 Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
  • 13 Department of Human Genetics, Cancer Biology Graduate Program, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 14 Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. [email protected] [email protected] [email protected].
  • 15 NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA. [email protected] [email protected] [email protected].
  • 16 Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA. [email protected] [email protected] [email protected].
PMID: 29769289 DOI: 10.1126/scitranslmed.aap8307
Abstract

Metastasis remains a leading cause of Cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of Cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple Cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human Cancer, and extends survival of mice in a metastatic pancreatic Cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic Cancer.

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